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EP0108295A1 - Orale Dosierungsform - Google Patents

Orale Dosierungsform Download PDF

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Publication number
EP0108295A1
EP0108295A1 EP83110343A EP83110343A EP0108295A1 EP 0108295 A1 EP0108295 A1 EP 0108295A1 EP 83110343 A EP83110343 A EP 83110343A EP 83110343 A EP83110343 A EP 83110343A EP 0108295 A1 EP0108295 A1 EP 0108295A1
Authority
EP
European Patent Office
Prior art keywords
mixture
fatty acid
potentiator
mono
lactam antibiotic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP83110343A
Other languages
German (de)
English (en)
French (fr)
Inventor
Charanjit Behl
George Beskid
Navnit Shah
Jacques Tossounian
Joel Unowsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0108295A1 publication Critical patent/EP0108295A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the present invention relates to an absorbable pharmaceutical preparation, wherein essentially orally inactive ⁇ -lactam antibiotics (including their pharmaceutically acceptable salts and their esters, ethers, and hydrates or hydrates of the salts) are converted into enterally or orally active products.
  • the preparation contains a combination of the chosen ß-lactam antibiotic with a certain potentiator.
  • the invention relates in particular to an absorbable preparation for enteral administration, characterized in that it contains a therapeutically effective amount of an essentially orally inactive ⁇ -lactam antibiotic in an absorption-increasing amount of a potentiator which consists of an aliphatic C 2 -C 18 fatty acid, a mono-, di- or triglyceride of a C 2 -C 12 fatty acid, a partial ester or full ester of propylene glycol, polyethylene glycol or a carbohydrate with a C 2 -C 12 fatty acid, a pharmaceutically acceptable ester or ether thereof or a mixture of the potentiators mentioned; if desired in conjunction with a pharmaceutically acceptable carrier.
  • the preparation is preferably in "enteric coated " form, in which case it is orally active and can be used for oral administration.
  • enteric coated form means that the preparation is provided with an enteric coating, either the dosage form itself, e.g. the capsule or tablet, or the two components, i.e. the ⁇ -lactam antibiotic or the potentiator, as will be explained in more detail below.
  • the invention also relates to a method for converting substantially orally inactive ⁇ -lactam antibiotics into enterally active products, characterized in that the aforementioned antibiotic is combined with an absorption-increasing amount of a potentiator, which consists of an aliphatic C 2 -C 18 fatty acid , a mono-, di- or triglyceride of a C 2 -C 12 fatty acid, a partial or total ester of propylene glycol, polyethylene glycol or a carbohydrate with a C 2 -C 12 fatty acid, a pharmaceutically acceptable ester or ether thereof or one Mixture of the potentiators mentioned; and, if desired, the combination product is combined with a pharmaceutically acceptable carrier.
  • a potentiator which consists of an aliphatic C 2 -C 18 fatty acid , a mono-, di- or triglyceride of a C 2 -C 12 fatty acid, a partial or total ester of propylene glyco
  • the combination product is preferably converted to "enteric coated” form, the product obtained being orally active and can be used for oral administration.
  • Preferred potentiators are saturated C 6 -C 12 fatty acids, unsaturated C 16 -C 18 fatty acids, mono-, di- or triglycerides of C S -C 12 fatty acids or mixtures thereof, edible oils with the potentiators mentioned and mixtures thereof; the preferred potentiators are mono- and diglyceride mixtures of C 8 / C 10 saturated fatty acids with a predominant proportion of monoglyceride.
  • the glyceride mixture content is preferably in the range between approximately 33 and approximately 98% by weight of the preparation, preferably approximately 89% by weight of the preparation.
  • Belgian Patent No. 567,598 discloses an oral (suspension) or parenteral method for administration by combining an antibiotic, e.g. a penicillin, with a fatty acid glyceride mixture, preferably a triglyceride mixture. According to the invention, however, it was found that unexpectedly high antibiotic blood levels can be achieved by using an "enteric" system in connection with the antibiotic / potentiator combination. This finding is essential because it has also been found that therapeutically unacceptable low antibiotic blood levels are obtained when the ⁇ -lactam antibiotic / potentiator combination is administered as a solution / suspension, as shown below.
  • ⁇ -lactam antibiotics means compounds with a ⁇ -lactam ring as the central structural element, ie the structural element which can be substituted in different ring positions and / or condensed with other ring systems which may themselves be substituted or unsubstituted.
  • Some examples of known ⁇ -lactam antibiotics are penicillins, cephalosporins, for example ceftriaxone, monocyclic ⁇ -lactams, for example azthreonam; Thienamycin and its derivatives and the clavulanic acid derivatives, including the pharmaceutically acceptable salts of the compounds mentioned.
  • the potentiator is, for example, a C 2 -C 18 straight-chain or branched-chain or saturated or unsaturated fatty acid.
  • fatty acids are butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, lauroleic acid (A9-dodecylenic acid), palmitoleic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, etc.
  • Preferred potentiators are C 2 -C 12 straight-chain fatty acids , saturated or unsaturated mono-, di- or triglycerides or mixtures thereof, partial esters or full esters of propylene glycol, polyethylene glycol and carbohydrates with C 2 -C 12 fatty acids and pharmaceutically acceptable esters or ethers of these mono- or diglycerides.
  • fatty acids represents a group of saturated or unsaturated, monobasic aliphatic carboxylic acids which form esters with glycerol or other alcohols, resulting in fats, oils, waxes and other lipids.
  • glycolides refers to esters of glycerin, including fats and oils, in which up to three molecules of fatty acid with one molecule of glycerin are bound. Although the majority of the same fatty acid is used, mixed fatty acid glycerides can be used. When using such glycerides of mixed fatty acids, optically active compounds can occur which also form part of the present invention.
  • esters and ethers of the mono- and diglycerides mentioned or the partial esters mentioned can also be used as potentiators.
  • Such esters and ethers can be represented by the formulas wherein R and R 'C 2 -C 12 fatty acid residues can have the same or different meanings and R "O represents an ester or ether group.
  • Suitable esterification agents are, for example, those which are formed from pharmaceutically acceptable weak acids /, such as tartaric acid and its diacetyl derivatives, acetic acid, ascorbic acid and citric acid or phosphoric acids with a monophosphate group which can form a monophosphate ester.
  • pharmaceutically acceptable weak acids / such as tartaric acid and its diacetyl derivatives, acetic acid, ascorbic acid and citric acid or phosphoric acids with a monophosphate group which can form a monophosphate ester.
  • Suitable ethers can be formed by reacting the mono- or dihydroxy function or the mono- or diglyceride with a reactive lower alkyl, alkenyl, alkynyl, aryl or substituted aryl compound, the corresponding pharmaceutically acceptable ether being formed. This implementation takes place in a manner known per se.
  • Rats weighing 250 g are given 20 mg / kg of the ⁇ -lactam antibiotic intravenously, orally and enterally.
  • the antibiotics are placed in distilled water or in one of the potentiators described above, for example CAPMUL 8210 or CAPMUL MCM90 (trademark of Stokely-Van Camp Inc., Columbus, Ohio), ie mixtures of mono- and diglycerides with C. 8 / C 10 saturated fatty acids with 70 or 90% monoglyceride, and administered to 0.025 to 1.0 ml.
  • Intravenous administrations of 0.5 ml were carried out as controls.
  • the antibiotic was used as a vehicle in distilled water or in one of the potentiators described above.
  • the plasma levels of the preparations prepared in the above manner after the various modes of administration were initially measured by cardiac puncture of the rats using a heparinized syringe. Subsequently, three rats were either killed and bled, or blood samples were taken from the tail at different intervals; the blood samples were pooled and centrifuged immediately. Blood monkeys were taken individually from the vein and femoral artery using a heparinized syringe. The blood samples containing antibiotics were examined using microbiological "large plate” analysis according to Lees and Tootill, Analyst 80, pages 95, 110 and 531 (1955). In the case of ceftriaxone, the sample was deproteinized by adding acetonitrile before analysis. E. coli 1346 was used as the microorganism for determining the plasma levels of ceftriaxone.
  • the first table shows the blood levels of ceftriaxone (acid form) in the rat and also the significantly higher blood levels when enteral administration of the antibiotic in CAPMUL 8210 compared to enteral administration of the antibiotic in water.
  • the second table shows in the rat the blood levels after administration of the sodium salt of ceftriaxone intravenously in water and again the considerably higher blood levels after enteral administration of the antibiotic in CAPMUL 8210 compared to enteral administration in water. Blood levels were also obtained after oral administration of the sodium salt of ceftriaxone in suspension with CAPMUL 8210, although unacceptably low. This corresponds to the information in Belgian patent No. 567,598 mentioned above.
  • the third table in the rat shows the results of enteral absorption of the sodium salt of ceftriaxone in suspension with other glyceride potentiators, including CAPMUL MCM90 (similar composition to CAPMUL 8210, but with about 90% monoglycerides compared to the 70% in CAPMUL 8210) .
  • the fourth table shows the blood levels of the sodium salt of ceftriaxone in a second species, the squirrel monkey.
  • the blood levels are specified for the N a-triumsalz of ceftriaxone after intravenous administration in water, after enteral administration, in CAPMUL 8210 or water, and after oral administration in suspension with CAPMUL 8210 and also in "enteric coated” hard gelatine capsules mg 20 Sodium salt of ceftriaxone in suspension with 100 ⁇ g CAPMUL 8210. Similar to the rat, after enteral administration of the sodium salt of ceftriaxone in CAPMUL 8210, significant blood levels were reached in the monkey, but not when the antibiotic was administered in water.
  • Dosage forms in the range from about 25 to about 2000 mg, preferably 50 to about 500 mg, of ⁇ -lactam antibiotic with the potentiator / carrier are used for use in human medicine.
  • An in vitro model for determining transport characteristics and thereby identifying usable carriers for the systemic delivery of the ⁇ -lactam antibiotics consists of a cell for measuring the permeability of a synthetic membrane in different carriers and at different concentrations of the antibiotic.
  • the model used is described in Behl et al., Journal of Investigative Dermatology 75, pages 346-352, 1980 and Durrheim et al., Journal of Pharmaceutical Sciences 69, No. 7, pages 781-786, 1980.
  • As a synthetic membrane uses a siloxane liquid membrane.
  • the cell consists of a container with two compartments and the membrane in between.
  • the receiving compartment contains a pH 7.4 buffer (Clarks-Subs buffer) and the donor compartment contains the selected potentiator / carrier, ie CAPMUL 8210 or diacetin, etc., with a C 1 -C 8 alkanol as lipophilicity-increasing agent.
  • Radio-labeled ß-lactam antibiotic is used in the Donor compartment presented. At zero time, samples are taken from the recipient compartment at certain time intervals. The measured amount of antibiotics in the recipient compartment is shown as a function of time in a diagram. The curve is linear and is used to calculate the permeability coefficient (P value) according to Fick's first law of diffusion.
  • a buffer / buffer control is used for comparison purposes.
  • the effectiveness of the carrier is a function of the P-value, ie a P-value greater than that of the buffer / buffer control indicates an increase in absorption.
  • the permeability coefficients of various potentiators / carriers as a 50% mixture with CAPMUL 8210 are as follows:
  • the ß-lactam antibiotic / potentiator mixture is administered orally using a fixed "enteric coated” dosage form in order to protect the ß-lactam antibiotic from gastric acid.
  • the carriers used for this are primarily in liquid form, but can be in solid form.
  • the mixtures can be filled into hard or soft capsules or the liquid carrier can be adsorbed on a solid carrier, for example on starch, in order to maintain a flow capable powder and then filled into the capsules mentioned or compressed into tablets with a suitable "enteric coating".
  • Other dosage forms may include "enteric coated” or non-"enteric coated” systems, i.e. Capsules or tablets in which the ß-lactam antibiotic and the potentiator themselves are “enteric coated”.
  • the "enteric coating” of the individual ⁇ -lactam antibiotic and / or potentiator can be achieved by using microencapsulated forms of the ⁇ -lactam and / or potentiator in order to obtain a flowable powder for filling in hard or soft capsules or for compression as tablets be accomplished.
  • a possible embodiment is an "enteric coated” microcapsule or bead-form of the ⁇ -lactam antibiotic either alone or as a suspension in a liquid potentiator, which mixture can then be encapsulated in an "enteric coated” or non-"enteric coated” capsule .
  • the preparations mentioned are encased in "enteric coating” materials so that the ß-lactam antibiotic is protected from the gastric juice and the optimal delivery of the ß-lactam / potentiator combination in the intestine is ensured.
  • the "enteric coating” material is not affected by the gastric juice, but is dissolved in the intestinal juice, whereby the active ingredient is released.
  • the effectiveness of such "enteric coated” products can be determined using known USP methods.
  • enteric coating materials can be used with or without plasticizers, such as acetylated glycerides, diethyl phthalate, etc., using methods known to those skilled in the art.
  • the “enteric coating” is applied to about 1-10%, preferably 2-8% of the capsule or tablet weight.
  • ⁇ -lactam antibiotic / potentiator ratios between about 1:32 to about 1: 0.5, preferably 1:16 to 1: 3, in particular about 1: 8, are used. As noted above, significant rat antibiotic levels are achieved with an antibiotic / potentiator ratio up to about 1: 100.
  • the preparations according to the invention can also contain auxiliaries known per se in order to achieve a desired consistency.
  • the preparations according to the invention can be solid or liquid formulations for oral administration.
  • they can be in the form of ordinary capsules or "enteric coated” capsules, microcapsules or beadlets, or tablets, such as “enteric coated” tablets or tablets with an "enteric coated” microencapsulated mixture of potentiator and ⁇ -lactam antibiotic, or the two components can each be "enteric coated” by themselves.
  • These forms of preparation can additionally contain conventional pharmaceutical carriers and additives, in particular viscosity-improving and / or structure-forming or matrix-forming additives in order to maintain a suitable viscosity and physical structure.
  • Suitable additives are, for example, thickeners, such as, for example, highly disperse silica (for example the commercial products "37 Aerosil”), bentonites, colloidal clay, carboxymethyl celluloses, modified montmorillonites, for example alkylammonium salts of montmorillonites (for example the commercial products "Bentone”), in which the alkyl group 16- Contain 18 carbon atoms, organic thickening and structure-forming agents, such as saturated higher fatty acids and alcohols with, for example, 12-20 carbon atoms, such as stearic or palmitic acid, stearyl or cetyl alcohol, waxes such as beeswax, synthetic esters of higher fatty acids and higher fatty alcohols, walnut fat, monoglycerides of saturated or unsaturated higher fatty acids, e.g.
  • thickeners such as, for example, highly disperse silica (for example the commercial products "37 Aerosil”), bentonites, colloidal clay, carboxymethyl cellulose
  • Monoglycerides of stearic acid, palmitic acid or oleic acid, partial glycerides of polyhydroxy fatty acids eg the commercial products "Softigen 701"
  • gel-forming agents such as aluminum stearate
  • dispersants such as anionic, nonionic and cationic foam generators
  • emulsifiers such as lecithin, and similar salts .
  • the preparations can also contain pharmaceutical adjuvants, for example binding agents or lubricants for tableting, stabilizers, for example EDTA, antioxidants, for example ascorbic acid, flavoring agents, preservatives, for example methyl or propyl paraben, and buffers, for example phosphates.
  • Dyes that can be used are, for example, the acceptable "food, drug or cosmetic" dyes.
  • titanium dioxide can be used as an opacifier.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP83110343A 1982-10-15 1983-10-17 Orale Dosierungsform Withdrawn EP0108295A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/434,452 US4525339A (en) 1982-10-15 1982-10-15 Enteric coated oral dosage form
US434452 1982-10-15

Publications (1)

Publication Number Publication Date
EP0108295A1 true EP0108295A1 (de) 1984-05-16

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ID=23724297

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83110343A Withdrawn EP0108295A1 (de) 1982-10-15 1983-10-17 Orale Dosierungsform

Country Status (14)

Country Link
US (1) US4525339A (no)
EP (1) EP0108295A1 (no)
JP (1) JPS59104312A (no)
KR (1) KR840006437A (no)
AU (1) AU2019283A (no)
DK (1) DK473183A (no)
FI (1) FI833728L (no)
GR (1) GR82301B (no)
IL (1) IL69960A0 (no)
MC (1) MC1550A1 (no)
NO (1) NO833757L (no)
PT (1) PT77503A (no)
ZA (1) ZA837307B (no)
ZW (1) ZW22183A1 (no)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0152896A2 (de) * 1984-02-22 1985-08-28 F. Hoffmann-La Roche Ag Suppositorien enthaltend Ceftriaxon
EP0225189A2 (en) * 1985-11-29 1987-06-10 R.P. Scherer Corporation Targeted enteral delivery system
EP0287036A2 (en) * 1987-04-13 1988-10-19 Ono Pharmaceutical Co., Ltd. New pharmaceutical compositions comprising esters or amides as active ingredients
EP0370481A2 (de) * 1988-11-22 1990-05-30 F. Hoffmann-La Roche Ag Pharmazeutische Präparate zur verbesserten Resorption antibakterieller Verbindungen
EP0418674A1 (de) * 1989-09-11 1991-03-27 F. Hoffmann-La Roche Ag Pharmazeutische Präparate zur verbesserten Resorption anti-bakterieller Verbindungen
AT393955B (de) * 1990-03-30 1992-01-10 Martin Dr Leixnering Einrichtung zur nachbehandlung frischer beugesehnenverletzungen
EP0548558A2 (en) * 1991-12-20 1993-06-30 American Cyanamid Company Compositions containing surfactants as potentiating agents for the treatment of mammalian diseases
US5817338A (en) * 1994-07-08 1998-10-06 Astra Aktiebolag Multiple unit tableted dosage form of omeprazole
US6132770A (en) * 1996-01-08 2000-10-17 Astrazeneca Ab Multiple unit effervescent dosage forms comprising proton pump inhibitor
US6132771A (en) * 1996-01-08 2000-10-17 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent
US6136344A (en) * 1995-02-06 2000-10-24 Astra Aktiebolag Oral pharmaceutical dosage form
US6183776B1 (en) 1996-01-08 2001-02-06 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
US6365184B1 (en) 1996-01-08 2002-04-02 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60146825A (ja) * 1984-01-10 1985-08-02 Asahi Chem Ind Co Ltd 経口医薬製剤
US4760059A (en) * 1985-08-05 1988-07-26 Hoffmann-La Roche Inc. Rectal dosage form
SE457326B (sv) * 1986-02-14 1988-12-19 Lejus Medical Ab Foerfarande foer framstaellning av en snabbt soenderfallande kaerna innehaallande bl a mikrokristallin cellulosa
JP2514950B2 (ja) * 1986-03-10 1996-07-10 エフ・ホフマン―ラ ロシユ アーゲー 化学修飾蛋白質，その製造法および中間体
US6024983A (en) * 1986-10-24 2000-02-15 Southern Research Institute Composition for delivering bioactive agents for immune response and its preparation
US5075109A (en) * 1986-10-24 1991-12-24 Southern Research Institute Method of potentiating an immune response
ES2061623T3 (es) * 1987-03-02 1994-12-16 Brocades Pharma Bv Procedimiento para la obtencion de una composicion farmaceutica y un granulado farmaceutico.
IE59934B1 (en) * 1987-06-19 1994-05-04 Elan Corp Plc Liquid suspension for oral administration
DE3729299A1 (de) * 1987-09-02 1989-03-23 Beiersdorf Ag Transdermales therapeutisches system
US5009894A (en) * 1988-03-07 1991-04-23 Baker Cummins Pharmaceuticals, Inc. Arrangement for and method of administering a pharmaceutical preparation
US5260271A (en) * 1988-06-22 1993-11-09 Applied Microbiology, Inc. Nisin compositions for use as enhanced broad range bactericides
US4925674A (en) * 1988-08-25 1990-05-15 Himedics, Inc. Amoxicillin microencapsulated granules
US5190748A (en) * 1988-11-22 1993-03-02 Hoffmann-La Roche Inc. Absorption enhancement of antibiotics
US6482516B1 (en) * 1993-07-20 2002-11-19 Banner Pharmacaps, Inc. Enrobed tablet
US5160742A (en) * 1991-12-31 1992-11-03 Abbott Laboratories System for delivering an active substance for sustained release
US5382435A (en) * 1993-03-24 1995-01-17 Southwest Research Institute Microparticulate pharmaceutical delivery system
US5318781A (en) * 1993-04-06 1994-06-07 Hoffmann-La Roche Inc. Absorption enhancement of antibiotics
US5559110A (en) * 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
US5482718A (en) * 1994-03-23 1996-01-09 Hoffmann-La Roche Inc. Colon-targeted delivery system
US5447729A (en) * 1994-04-07 1995-09-05 Pharmavene, Inc. Multilamellar drug delivery systems
GB9407386D0 (en) 1994-04-14 1994-06-08 Smithkline Beecham Plc Pharmaceutical formulation
ES2301477T3 (es) * 1999-02-22 2008-07-01 Merrion Research I Limited Forma de dosificacion oral solida que contiene un potenciador.
US8119159B2 (en) * 1999-02-22 2012-02-21 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
US20070148228A1 (en) * 1999-02-22 2007-06-28 Merrion Research I Limited Solid oral dosage form containing an enhancer
US7658938B2 (en) * 1999-02-22 2010-02-09 Merrion Reasearch III Limited Solid oral dosage form containing an enhancer
NZ523276A (en) * 2000-06-21 2005-02-25 Cubist Pharm Inc Compositions and methods to improve the oral absorption of antimicrobial agents
US6248360B1 (en) 2000-06-21 2001-06-19 International Health Management Associates, Inc. Complexes to improve oral absorption of poorly absorbable antibiotics
US7527807B2 (en) * 2000-06-21 2009-05-05 Cubist Pharmaceuticals, Inc. Compositions and methods for increasing the oral absorption of antimicrobials
JP4812225B2 (ja) * 2000-07-11 2011-11-09 塩野義製薬株式会社 生理活性ペプチド含有腸溶性製剤
CA2446622C (en) * 2001-05-11 2012-08-14 Elan Corporation, Plc Isostearic acid salts as permeation enhancers
CA2446619C (en) * 2001-05-11 2011-04-26 Elan Corporation, Plc Permeation enhancers
KR100540035B1 (ko) * 2002-02-01 2005-12-29 주식회사 태평양 다단계 경구 약물 방출 제어 시스템
WO2003090717A1 (en) * 2002-04-23 2003-11-06 Nanotherapeutics, Inc Process of forming and modifying particles and compositions produced thereby
TWI355276B (en) * 2003-01-14 2012-01-01 Akira Tsuji Gastrointestinal absorption enhancer mediated by p
US20050152969A1 (en) * 2004-01-08 2005-07-14 Chiprich Timothy B. Colored liquid-filled soft capsules and method of manufacture thereof
NZ580951A (en) * 2005-04-29 2011-06-30 Cubist Pharm Inc Therapeutic compositions
KR101191322B1 (ko) * 2006-04-07 2012-10-16 메리온 리서치 Ⅲ 리미티드 증진제를 함유하는 고형 경구용 투여 제형
US20070292512A1 (en) * 2006-06-09 2007-12-20 Merrion Research Ii Limited Solid Oral Dosage Form Containing an Enhancer
US20080260820A1 (en) * 2007-04-19 2008-10-23 Gilles Borrelly Oral dosage formulations of protease-resistant polypeptides
KR101545874B1 (ko) 2007-09-03 2015-08-20 나노테라퓨틱스, 인코포레이티드 난용성 약물의 전달을 위한 입상 조성물
WO2009052391A1 (en) * 2007-10-19 2009-04-23 Purdue Research Foundation Solid formulations of crystalline compounds
CA2723558A1 (en) * 2008-05-07 2009-11-12 Merrion Research Iii Limited Compositions of gnrh related compounds and processes of preparation
CA2751854A1 (en) * 2009-02-25 2010-09-02 Merrion Research Iii Limited Composition and drug delivery of bisphosphonates
US20110142889A1 (en) * 2009-12-16 2011-06-16 Nod Pharmaceuticals, Inc. Compositions and methods for oral drug delivery
CA2784120A1 (en) 2009-12-16 2011-07-14 Nod Pharmaceuticals, Inc. Compositions and methods for oral drug delivery
US20110182985A1 (en) * 2010-01-28 2011-07-28 Coughlan David C Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof
US9089484B2 (en) * 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
US8802114B2 (en) 2011-01-07 2014-08-12 Merrion Research Iii Limited Pharmaceutical compositions of iron for oral administration
WO2013052010A1 (en) * 2011-10-03 2013-04-11 Agency For Science, Technology And Research Antibiotic composition and its uses
WO2016120378A1 (en) 2015-01-29 2016-08-04 Novo Nordisk A/S Tablets comprising glp-1 agonist and enteric coating
WO2019036770A1 (en) * 2017-08-24 2019-02-28 University Of South Australia ANTIMICROBIAL COMPOSITIONS AND METHODS OF USE

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE567598A (no) *
FR2206943A1 (no) * 1972-11-18 1974-06-14 Sumitomo Chemical Co
FR2320749A1 (fr) * 1975-08-14 1977-03-11 Beecham Group Ltd Composition veterinaire
FR2350836A1 (fr) * 1976-05-13 1977-12-09 Shionogi & Co Preparation de cefalexine a longue duree d'action pour le traitement efficace d'infections bacteriennes sensibles a la cefalexine
US4079131A (en) * 1975-01-02 1978-03-14 American Home Products Corporation Permanent suspension pharmaceutical dosage forms
GB2015339A (en) * 1978-03-07 1979-09-12 Sandoz Ltd Compositions comprising mono-cyclic peptides
US4273763A (en) * 1978-01-23 1981-06-16 Efamol Limited Pharmaceutical and dietary compositions

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2476351A (en) * 1945-06-07 1949-07-19 Parke Davis & Co Injectable penicillin compositions
US2487336A (en) * 1946-02-25 1949-11-08 William E Hinds Penicillin product
US2443778A (en) * 1947-04-21 1948-06-22 Monroe J Romansky Preparations for penicillin therapy
US2566200A (en) * 1947-06-07 1951-08-28 Commercial Solvents Corp Oral therapeutic tablets
US2507193A (en) * 1949-05-17 1950-05-09 Bristol Lab Inc Penicillin product
US2805977A (en) * 1955-01-04 1957-09-10 Smith Kline French Lab Sustained release pharmaceutical preparation
US2902407A (en) * 1955-06-14 1959-09-01 Commercial Solvents Corp Wax-coated penicillin product
US2864744A (en) * 1955-09-02 1958-12-16 American Home Prod Penicillin in solid dosage unit form
US3016330A (en) * 1955-11-10 1962-01-09 Novo Terapeutisk Labor As Therapeutical antibiotic composition
US2951014A (en) * 1957-01-03 1960-08-30 Upjohn Co Process for a stable oil suspension
US3402240A (en) * 1957-06-25 1968-09-17 Pfizer & Co C Medicinal tablet and process of making same
NL297631A (no) * 1963-06-03
US3849569A (en) * 1965-12-02 1974-11-19 Glaxo Lab Ltd Composition containing procaine penicillin
GB1226555A (no) * 1967-08-08 1971-03-31
US3626056A (en) * 1967-11-02 1971-12-07 Bristol Myers Co Oral antibiotic product
US3549746A (en) * 1967-11-02 1970-12-22 Bristol Myers Co Antibiotic composition
US3538215A (en) * 1969-06-13 1970-11-03 Allied Chem Stabilized antibiotic in liquid ruminant feed supplement
GB1312918A (en) * 1969-07-08 1973-04-11 Beecham Group Ltd Veterinary treatment
US3696189A (en) * 1970-05-18 1972-10-03 Frank M Snyder Stabilized antibiotic and method
US3655864A (en) * 1970-09-21 1972-04-11 Smith Kline French Lab Glyceryl tristerate and higher fatty acid mixture for improving digestive absorption
GB1413186A (en) * 1973-06-27 1975-11-12 Toyo Jozo Kk Process for encapsulation of medicaments
US4145429A (en) * 1974-09-21 1979-03-20 Beecham Group Limited Oral veterinary preparations
JPS5231981A (en) * 1975-08-18 1977-03-10 Takeda Chem Ind Ltd Microcapsule preparation method
JPS5283924A (en) * 1976-01-01 1977-07-13 Sumitomo Chem Co Ltd Preparation of pharmaceuticals for rectal infusion containing penicill ins and cephalosporins
JPS6055486B2 (ja) * 1976-02-28 1985-12-05 富山化学工業株式会社 β−ラクタム環を有する化合物の直腸投与用組成物
DE2654844A1 (de) * 1976-12-03 1978-06-08 Kali Chemie Pharma Gmbh Verfahren zur herstellung fester loesungen von arzneistoffen zur oralen und rektalen applikation
US4250166A (en) * 1977-05-27 1981-02-10 Shionogi & Co., Ltd. Long acting preparation of cefalexin for effective treatments of bacterial infection sensitive to cefalexin
IL58462A0 (en) * 1978-10-27 1980-01-31 Beecham Group Ltd Intramammary compositions comprising a penicillin
GB2051574B (en) * 1979-05-10 1984-01-18 Kyoto Pharma Ind Adjuvant for promoting absorption of pharmacologically active substances through the rectum
JPS56104812A (en) * 1980-01-23 1981-08-20 Sankyo Co Ltd Production of cephalosporin compound preparation for rectal infusion
JPS5799519A (en) * 1980-12-12 1982-06-21 Toyo Jozo Co Ltd Stable suppository and its preparation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE567598A (no) *
FR2206943A1 (no) * 1972-11-18 1974-06-14 Sumitomo Chemical Co
US4079131A (en) * 1975-01-02 1978-03-14 American Home Products Corporation Permanent suspension pharmaceutical dosage forms
US4079138A (en) * 1975-01-02 1978-03-14 American Home Products Corporation Permanent suspension pharmaceutical dosage forms
FR2320749A1 (fr) * 1975-08-14 1977-03-11 Beecham Group Ltd Composition veterinaire
FR2350836A1 (fr) * 1976-05-13 1977-12-09 Shionogi & Co Preparation de cefalexine a longue duree d'action pour le traitement efficace d'infections bacteriennes sensibles a la cefalexine
US4273763A (en) * 1978-01-23 1981-06-16 Efamol Limited Pharmaceutical and dietary compositions
GB2015339A (en) * 1978-03-07 1979-09-12 Sandoz Ltd Compositions comprising mono-cyclic peptides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 73, Nr. 2, 13. Juli 1970, Seite 253, Nr. 7218t, Columbus, Ohio, US & ZA - A - 68 05 560 (BRISTOL-MYERS CO.) 29-08-1969 *
CHEMICAL ABSTRACTS, Band 86, Nr. 12, 21. März 1977, Seite 396, Nr. 78631b, Columbus, Ohio, US *
CHEMICAL ABSTRACTS, Band 97, Nr. 18, November 1982, Seiten 890, Nr. 150678u, Columbus, Ohio, US *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0152896A3 (de) * 1984-02-22 1986-01-22 F. Hoffmann-La Roche Ag Suppositorien enthaltend Ceftriaxon
AU572610B2 (en) * 1984-02-22 1988-05-12 F. Hoffmann-La Roche Ag Suppositories comprising ceftriazone or its derivatives
EP0152896A2 (de) * 1984-02-22 1985-08-28 F. Hoffmann-La Roche Ag Suppositorien enthaltend Ceftriaxon
EP0225189A2 (en) * 1985-11-29 1987-06-10 R.P. Scherer Corporation Targeted enteral delivery system
EP0225189A3 (en) * 1985-11-29 1987-12-16 R.P. Scherer Corporation Targeted enteral delivery system
US4910021A (en) * 1985-11-29 1990-03-20 R. P. Scherer Corporation Targeted enternal delivery system
EP0287036A2 (en) * 1987-04-13 1988-10-19 Ono Pharmaceutical Co., Ltd. New pharmaceutical compositions comprising esters or amides as active ingredients
EP0287036A3 (en) * 1987-04-13 1988-11-30 Ono Pharmaceutical Co., Ltd. New pharmaceutical compositions comprising esters or amides as active ingredients
EP0370481B1 (de) * 1988-11-22 1993-09-22 F. Hoffmann-La Roche Ag Pharmazeutische Präparate zur verbesserten Resorption antibakterieller Verbindungen
EP0370481A2 (de) * 1988-11-22 1990-05-30 F. Hoffmann-La Roche Ag Pharmazeutische Präparate zur verbesserten Resorption antibakterieller Verbindungen
EP0418674A1 (de) * 1989-09-11 1991-03-27 F. Hoffmann-La Roche Ag Pharmazeutische Präparate zur verbesserten Resorption anti-bakterieller Verbindungen
AT393955B (de) * 1990-03-30 1992-01-10 Martin Dr Leixnering Einrichtung zur nachbehandlung frischer beugesehnenverletzungen
EP0548558A2 (en) * 1991-12-20 1993-06-30 American Cyanamid Company Compositions containing surfactants as potentiating agents for the treatment of mammalian diseases
EP0548558A3 (en) * 1991-12-20 1993-10-13 American Cyanamid Company Compositions containing surfactants as potentiating agents for the treatment of mammalian diseases
US5817338A (en) * 1994-07-08 1998-10-06 Astra Aktiebolag Multiple unit tableted dosage form of omeprazole
US6136344A (en) * 1995-02-06 2000-10-24 Astra Aktiebolag Oral pharmaceutical dosage form
US6132770A (en) * 1996-01-08 2000-10-17 Astrazeneca Ab Multiple unit effervescent dosage forms comprising proton pump inhibitor
US6132771A (en) * 1996-01-08 2000-10-17 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent
US6183776B1 (en) 1996-01-08 2001-02-06 Astra Aktiebolag Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate
US6365184B1 (en) 1996-01-08 2002-04-02 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID
US6613354B2 (en) 1996-01-08 2003-09-02 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID
US7488497B2 (en) 1996-01-08 2009-02-10 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID
US8114435B2 (en) 1996-01-08 2012-02-14 Astrazeneca Ab Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID

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IL69960A0 (en) 1984-01-31
AU2019283A (en) 1984-04-19
KR840006437A (ko) 1984-11-30
FI833728A0 (fi) 1983-10-13
US4525339A (en) 1985-06-25
PT77503A (en) 1983-11-01
DK473183A (da) 1984-04-16
FI833728L (fi) 1984-04-16
NO833757L (no) 1984-04-16
ZW22183A1 (en) 1985-04-17
DK473183D0 (da) 1983-10-13
GR82301B (no) 1984-12-13
JPS59104312A (ja) 1984-06-16
MC1550A1 (fr) 1984-08-31
ZA837307B (en) 1984-06-27

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